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A fatal case of Trichosporon asahii

fungemia and pneumonia in a kidney


transplant recipient during
caspofungin treatment
Mei-fang Yang,1,2 Hai-nv Gao,1,2 and Lan-juan Li1,2

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Abstract
Trichosporon asahii is an emerging opportunistic pathogen that is life-threatening
particularly for immunosuppressed patients. Only a few studies have described
Trichosporon infection in kidney transplant recipients. This study reports a
67-year-old male kidney transplant recipient who developed fatal fungemia and
pneumonia caused by T. asahii during caspofungin treatment. Although funguria is
benign, kidney transplant recipients are still at risk of T. asahii fungemia and invasive
T. asahii infection even if they are under antifungal therapy, particularly
echinocandins.

Keywords: funguria, organ transplant, opportunistic infection, invasive


fungal infection, antifungal therapy

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Background
Trichosporon asahii (formerly known as T. beigelii) is a rare opportunistic pathogen
associated with severe complications, particularly in immunosuppressed patients.1 To
our knowledge, only a few studies have described Trichosporon infection in kidney
transplant recipients.2–7 This study presents a 67-year-old male with an 8-year
history of kidney transplantation who developed T. asahii fungemia during
caspofungin treatment.

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Case presentation
A 67-year-old male was admitted to our hospital because of fever, cough, and
shortness of breath for 2 weeks. The patient received a renal transplant 8 years
previously because of end-stage renal disease caused by diabetic nephropathy. The
patient had hypertension and diabetes mellitus, which required antihypertensive
therapy and insulin use, respectively. The patient also received immunosuppressive
therapy. Two months before admission, regular follow-up showed 138 μmol/L
creatinine values and normal chest computed tomography (CT) scan. Before
admission, his antirejection therapy regimen included mycophenolate mofetil (500 mg
in the morning and 750 mg at night), tacrolimus (0.5 mg daily), and prednisone (7.5
mg daily). Upon admission, the patient presented with dyspnea, body temperature of
38.0°C, respiratory rate of 28 breaths/minute, oxygen saturation of 98% on 3 L via
nasal cannula, blood pressure of 134/71 mmHg, and a heart rate of 101 beats/minute.
Physical examination revealed pulmonary moist rale and pitting edema in the lower
extremities. The white blood cell count was 8.2×109 cells/L (89.5% neutrophils),
hemoglobin level was 114 g/L, and platelet count was 187×109 cells/L. Blood
biochemistry revealed potassium ion and creatinine values of 6.59 mmol/L and 193
μmol/L, respectively. C reactive protein was 199 g/L, and human immunodeficiency
virus (HIV) test was negative. Chest X-ray revealed pleural effusion and bilateral
airspace opacities consistent with pneumonia. The primary diagnosis was severe
pneumonia. Thus, the antirejection regimen was adjusted to methylprednisolone (80
mg every 12 hours). The patient empirically started intravenous imipenem/cilastatin
(500 mg every 8 hours) and orally received trimethoprim– sulfamethoxazole (160 mg
of trimethoprim component twice daily). The patient also received continuous
venovenous hemodialysis. However, the patient continued to deteriorate and required
mechanical ventilation for respiratory failure. Three days after admission, the patient
was transferred to the intensive care unit because of severe pneumonia accompanied
with respiratory failure and heart failure. Chest CT scan showed discrete scattered
patchy consolidation in both lungs (Figure 1). The patient received sputum and blood
culture daily. Sputum culture showed the growth of Candida albicans for three tests.
All blood culture tests yielded negative results from Day 1 to Day 8. Thus, the
antimicrobial regimen was adjusted to intravenous teicoplanin (400 mg twice daily for
3 days; 400 mg daily thereafter), imipenem/cilastatin (500 mg once every 6 hours),
trimethoprim–sulfamethoxazole (160 mg of trimethoprim component twice daily),
and caspofungin (loading dose, 70 mg; 50 mg daily thereafter). Despite the aggressive
therapy, the patient died 10 days after admission because of sepsis, resulting in
multiple organ failure. The two sets of blood cultures and one sample of sputum
collected on Day 9 showed the growth of T. asahii. This result was confirmed after
the patient died using a Vitek 2 YST yeast identification kit (Vitek 2 YST,
bioMerieux VITEK-2; Marcy l’Etoile, Durham, UK). Antifungal susceptibility test
was performed using the microbroth dilution technique in accordance with the
guidelines of the Clinical and Laboratory Standards Institute. The results showed the
following minimum inhibitory concentrations (susceptibility breakpoints): 0.5 mg/L
(≤1) amphotericin B, 0.125 mg/L (≤0.125) itraconazole, 1 mg/L (≤8) fluconazole,
0.06 mg/L (≤1) voriconazole, and 4 mg/L (≤4) 5-fluorocytosine.
Figure 1

The chest computed tomography scan showed discrete scattered patchy


consolidation in both lungs.

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Discussion
Over the last few decades, Trichosporon spp. have been increasingly recognized as
opportunistic pathogens that can cause invasive infections, particularly in patients
with underlying hematological malignancies, bone marrow transplantation, organ
transplantation, extensive burns, HIV infection, and peritoneal dialysis.1 Systemic
infections caused by Trichosporon spp. are frequently associated with poor prognosis.
Six Trichosporon species, namely T. asahii, T. asteroides, T. cutaneum, T. inkin, T.
mucoides, and T. ovoides, cause superficial, mucosa-associated, invasive infections.1
T. asahii is currently the predominant species in invasive Trichosporon infections.1

We report a patient with T. asahii fungemia and suspected pneumonia who presented
an overwhelming sepsis during caspofungin therapy. To our knowledge, only a few
studies have described Trichosporon infection in kidney transplant recipients; such
infections are usually caused by T. beigelii and T. mucoides, and are associated with
skin lesions,2,3 funguria,4,5 wound infection,6 and vascular anastomosis.7 T. asahii
colonizes the urinary tract of renal transplant recipients.4 T. beigelii funguria, which
has been reported in renal transplant recipients, is usually benign and seldom
associated with invasive infections.5 Only two cases of disseminated Trichosporon
infection that causes skin lesions have been reported in renal transplant recipients.2,3
Mirza2 reported a 45-year-old male who presented with malaise, fever, and multiple
reddish nodules on the trunk and face 6 months after renal transplantation. Nodule
biopsy culture confirmed T. beigelii infection. Analogously, Nettles et al3 reported a
64-year-old man complaining about fever, fatigue, malaise, and several pruritic
papules on the lower limbs after renal transplantation; skin biopsy culture tested
positive for T. mucoides. Fluconazole was effective in the two cases. The most typical
skin lesions are multiple small nontender reddish–purple papules approximately 0.5
cm in diameter; with its progression, the nodule center becomes necrotic.2,3 However,
the typical skin lesions were absent in our patient.

The common risk factors of T. asahii are granulocytopenia (particularly in


hematological malignancies), organ transplantation, HIV infection, extensive burns,
cortico steroid therapy, and peritoneal dialysis.1 In the present case, the patient had
some risk factors for systematic fungus infection. These factors included organ
transplantation, mechanical ventilation, broad-spectrum antibiotic therapy, continuous
venovenous hemodialysis, and steroid therapy. However, neutropenia was not
observed throughout the hospitalization.
The treatment for invasive Trichosporon infections remains difficult. Despite
antifungal therapy, the mortality rate ranges from 42% to 87.5%.1 The optimal
therapy regimen for trichosporonosis has yet to be identified. Echinocandins are
ineffective against Trichosporon spp.,8 with minimum inhibitory concentration values
ranging from 16 μg/mL to 64 μg/mL for caspofungin from clinical isolates.3,9–12
The use of echinocandins leads to a significant selective pressure that is favorable for
opportunistic fungi, including Trichosporon, with resistance to such agents; reports of
Trichosporon infections in patients who are receiving micafungin or caspofungin have
emerged.9,10 Increasing data indicated that amphotericin B has limited activity
against Trichosporon spp. in vitro and in vivo.13 Moreover, in vitro susceptibility
studies on amphotericin B for Trichosporon isolates are not always correlated with
good clinical response.13 Triazoles are currently the drug of choice for the treatment
of Trichosporon infections. The clinical experience with triazoles is encouraging.
Previous cases reported successful treatment of disseminated trichosporonosis using
voriconazole, posaconazole, and fluconazole.2,3,6,14 Recent studies have shown that
voriconazole is highly active against T. asahii isolates in vitro and in clinical settings;
these isolates include those with reduced susceptibility to amphotericin B,
itraconazole, and fluconazole.14,15 A recent study with head-to-head comparison of
five triazoles has shown that the most active is voriconazole, followed by itraconazole,
posaconazole, isavuconazole, and fluconazole.16

Some clinical trials failed to treat disseminated T. asahii infection using amphotericin
B or triazole alone. Thus, combined therapy has gained increasing attention for
treating trichosporonosis. Echinocandins alone have little to no activity against
Trichosporon spp.8 and are thus not recommended for trichosporonosis treatment;
however, a combination of echinocandins with amphotericin B or azoles exhibits in
vitro and in vivo antifungal effects. In vitro, the combination of
micafungin/caspofungin and amphotericin B against T. asahii is more effective than
using one drug only.11,12 A favorable response has been reported for the
combination of amphotericin B and caspofungin therapy in a patient with untreated
disseminated T. asahii infection; the patient was previously treated with amphotericin
B alone and subsequent voriconazole therapy.17 Using a murine model with
disseminated infection caused by T. asahii, Serena et al18 found that combining
micafungin with fluconazole significantly decreases the kidney fungal burden
compared with administering either drug alone. Thus, combined antifungal therapy
may be a potential strategy for treating disseminated trichosporonosis. Further
research should be performed to investigate the in vitro and in vivo activities of
antifungal drugs against Trichosporon spp.

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Conclusion
Although funguria is benign, kidney transplant recipients are still at risk of invasive T.
asahii infection even under antifungal therapy, particularly echinocandins. We
describe a breakthrough T. asahii infection in a kidney transplant recipient from the
People’s Republic of China during caspofungin therapy. Clinicians should be aware
that Trichosporon infections may develop in patients who are at risk of fungal
infection, particularly when such patients develop symptoms and signs of an
unexplained infection while undergoing echinocandin therapy. Triazoles, particularly
voriconazole alone or in combination, are currently the drugs of choice for treating
Trichosporon infections.

Trichosporon asahii, a Non-Candida


Yeast That Caused Fatal Septic Shock
in a Patient without Cancer or
Neutropenia
John R. Ebright Marilynn R. Fairfax Jose A. Vazquez

Clinical Infectious Diseases, Volume 33, Issue 5, 1 September 2001, Pages


e28–e30, https://doi.org/10.1086/322640

Published:

01 September 2001

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Abstract
Trichosporon asahii (formerly Trichosporon beigelii) is an emerging fungal pathogen
seen particularly in immunologically compromised patients. There are now ~100
reported cases of hematogenously disseminated infections with this life-threatening
yeast, and no effective antifungal therapy is available. The present case is unusual
because the patient did not have neutropenia or evidence of a malignancy.

Topic:

 antifungal agent
 septic shock
 cancer
 neutropenia
 trichosporon
 yeasts
 infection
 pathogenic organism
 candida

Issue Section:

Brief Reports
Candida species are now the fourth most frequently isolated nosocomial bloodstream
pathogens in the United States, following coagulase-negative staphylococci,
Staphylococcus aureus, and enterococci [1]. Trichosporon species, another yeast,
have been reported as a cause of fungemia, especially in patients who have
neutropenia and cancer. Trichosporonosis has been recognized with increased
frequency during the past 10–15 years and may resemble disseminated candidiasis
both in clinical presentation and in histopathologic appearance [2]. We report a case
that represents the clinical features and histopathologic findings resulting from
Trichosporon fungemia, but that differs from most reports published elsewhere in that
the patient did not have cancer or neutropenia.

A 53-year-old woman who was known to have hypertension and diabetes mellitus that
required insulin use was found in an unresponsive state at her home; her blood
pressure was 250/126 mm Hg. She was admitted to the intensive care unit, where her
blood pressure was brought under control within hours by use of nitroprusside.
Broad-spectrum antibiotics (cefepime and clin-damycin, followed by piperacillin and
vancomycin) were given, during an 18-day period, for a presumed left lower-lobe
pneumonia. On hospital day 6, her diabetes and hypertensive en-cephalopathy were
much improved, and she was transferred to a medicine ward. However, within 2 days,
complications, including progressive renal failure, thrombocytopenia, and status
epilepticus, required readmission to the intensive care unit. She underwent intubation
and was treated with dilantin, pentobar-bital, and gabapentin. In addition,
thrombocytopenia with a platelet nadir that reached 19,000 platelets/mm3 was
accompanied by bleeding from the mouth and gastrointestinal tract.

Extensive evaluation for the cause of thrombocytopenia, including bone marrow and
peripheral smear examination, was unrewarding. In particular, the diagnosis of
thrombotic throm-bocytopenic purpura could not be established. Renal failure of
uncertain cause required hemodialysis that involved use of a vascular catheter in the
groin. Total parenteral nutrition was initiated on hospital day 16. Toxic epidermal
necrolysis developed on hospital day 19, probably as a complication of dilantin use.
Treatment with high-dose iv corticosteroids was begun on hospital day 21. On
hospital day 24, the patient's status changed dramatically. She became hypotensive
and hypothermic and developed septic shock. The central catheters, which were in
place for most of the hospital stay, were suspected as the most likely source. Because
Candida species were considered the most likely infecting organisms, iv amphotericin
and fluconazole were added to the vancomycin regimen. The patient died on hospital
day 25. Blood samples that had been obtained the previous day for culture became
positive for Trichosporon asahii within 24 h. Samples obtained from 2 of the 3
vascular catheters and cultured and were found to be negative for Trichosporon
species. We suspect that the portal of entry was either one of the vascular catheters, or
compromised skin or mucous membrane.

Throughout the patient's hospital stay, she had never had neutropenia. Culture of
blood samples obtained on several occasions, including the day of admission and
hospital day 20, yielded negative results. Levels of serum immunoglobulins, including
IgG and IgM, were normal, as were complement levels (C3 and C4). Serological
testing for HIV was not done because permission could not be obtained; however, the
patient was not known to have risk factors for HIV.

Autopsy revealed hyphae with arthroconidia that were consistent with Trichosporon
species widely dispersed throughout the lungs and heart (figure 1). Trichosporon
species were also found in the bone marrow, lymph nodes, adrenal gland, kidney
(although not appearing extensive enough to account for renal failure), and thyroid
gland, but they were not found in the liver, spleen, pancreas, or brain. Also present
were micronodular cirrhosis (probably secondary to earlier alcohol use as well as
hepatitis C), diffuse and nodular glomerulosclerosis, acute pancreatitis, and an old
infarct of the right parietal cortex. The bone marrow revealed all cell lines present,
with only a modest decrease in megakaryocytes.

Figure 1

View largeDownload slide

Fungal elements in lung sections obtained at autopsy of patient with disseminated


Trichosporon asahii infection. A, Number of fungal elements in ischemic lung tissue,
including true hyphae, pseu-dohyphae, arthroconidia, and blastospores. B, True
hyphae. C, Arthrocon-idia. Original magnification, X2800.

The blood isolate was identified as T. asahii morphologically and by means of the
Vitek API 20C biochemical testing system (bioMérieux), both at the Detroit Medical
Center Microbiology laboratory and the fungal research laboratory of J.A.V.

In vitro studies of susceptibility to amphotericin B, flucon-azole, itraconazole, and


voriconazole were performed by use of the microbroth dilution technique and the
guidelines of the National Committee for Clinical Laboratory Standards [3]. MICs
were as follows: for amphotericin B, 2 mg/mL; flucona-zole, 1 mg/mL; itraconazole,
0.25 μg/mL; and voriconazole, 0.002 μg/mL.
Trichosporon species differ from Candida species in several respects: they do not
produce a germ tube, as does Candida albicans; they can form both hyaline septate
hyphae as well as pseudohyphae; and they produce arthroconidia (figure 1) [4].
Infections due to Trichosporon species may be superficial, involving hair shafts
known as “white piedra,” or disseminated, involving ≥1 visceral organs, as a result of
fungemia [4]. The organisms are found naturally in the soil and may also be part of
the normal human flora in stool or skin. Risk factors for hematogenous spread that
causes deep infections are use of immunosuppressive drugs and immunocompromised
states. It is especially common in patients with cancer. In fact, 80% of the ~100
reported cases of hematogenous T. asahii (formerly Trichosporon beigelii) infections
have occurred in patients with leukemia, most of whom had neutropenia [5]. Other,
less common predisposing factors include HIV infection, burns, organ transplantation,
peritoneal dialysis, and iv catheters [6].

Clinical features of disseminated infections include septic shock, pneumonia, renal


failure, chorioretinitis, and cutaneous lesions. Skin lesions usually appear as scattered
red papules, which may ulcerate and reveal fungal elements and vessel thrombosis on
biopsy. Renal involvement may manifest as proteinuria and hematuria as well as renal
failure [4, 7].

The mortality rates are very high (64% in a recent review in which 80% of the
patients had underlying leukemia [2]). Unfortunately, the most appropriate form of
therapy and the efficacy of treatment are uncertain. There is some evidence that
triazoles, such as itraconazole and fluconazole, are more active in vitro and perhaps
are more clinically effective than is amphotericin. However, at the present time, there
is no obviously effective antifungal drug [6, 8, 9].

Trichosporon species, especially T. asahii, are emerging pathogens that have


increasingly been reported in patients with cancer during the past 10–15 years.
Although it is not unique, our case demonstrates that Trichosporon species also may
cause life-threatening sepsis and widespread dissemination in patients who do not
have either neutropenia or cancer, but who, nevertheless, are at risk for an
opportunistic fungal infection due to chronic illness and compromised skin and
mucous membranes. In addition, a case of uterine trichosporonosis, also in a patient
with neither neutropenia nor cancer, was recently reported [10]. Moreover, in a recent
European study, Trichosporon species were the most common non-Candida cause of
fungemia at a national cancer institute [5]. Clinicians, therefore, need to have an
increased awareness of this organism and to note that trichosporonosis may appear
similar to disseminated candidiasis both in its clinical and histopathologic appearance
and in the type of patient infected. Treatment at this time appears to be less effective,
and the mortality rate is high.

Acknowledgments
We thank Ben True, Department of Photography, Detroit Medical Center, for
preparing the photomicrographs.
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